In vitro metabolic interaction studies: Experience of the Food and Drug Administration

A total of 194 new molecular entities approved by the Food and Drug Adminis tration between 1992 and 1997 were surveyed to determine the role of in vit ro metabolic interactions in the conduct of drug-drug interaction studies a nd to examine the methods used in these studies. Approximately 30% of the s ubmissions were found to have in vitro metabolism-based interaction studies , most of which were inhibitory in nature. Chemical inhibition was the most commonly used approach in studying drug interactions in vitro. In this art icle, an attempt to assess the quality of the chemical inhibition approach was made. Pour areas were found to be often overlooked: (1) incubation time and concentrations of the drug, (2) the difference between inhibition cons tant (k(i)) and 50% inhibitory concentration (IC50) values, (3) the substra te-dependent inhibition potential, and (4) the metabolic genotype or phenot ype of the liver donor. We discuss the pitfalls in estimating drug interact ions when these four areas are overlooked.